Soil-transmitted nematodes (STNs), including hookworm, whipworm, and Ascaris, are diseases of the world's most poor and are likely the most common human parasite (Stepek et al., 2006; Keiser and Utzinger, 2008; Hoetz et al., 2008). These parasites infect the gastrointestinal (GI) tracts of 1 in 3 people in the world and may cause as much morbidity as malaria. STN infections in children result in growth ad cognitive stunting and severely impact learning, school attendance, and future income potential. The World Health Assembly (WHA) in 2001 has urged the deworming of 75% at-risk school-aged children. Over 44 million hookworm-infected pregnant women are at an increased risk for premature delivery, low birth weight, maternal ill-health, and maternal death. Recent data suggest STN infections worsen the effects of malaria, HIV, and tuberculosis. STNS are one of the great neglected diseases of our time.
The soil microbe Bacillus thuringiensis (Bt) is a gram-positive, spore-forming bacterium characterized by parasporal crystalline protein inclusions. These inclusions often appear microscopically as distinctively shaped crystals and therefore, are referred to as crystal (Cry) proteins. Although harmless to vertebrates, many Cry proteins have been found to be highly toxic to a variety of invertebrate species, including free-living nematodes. In particular, soil transmitted nematodes are a legitimate class of therapeutic targets for Bt Cry proteins, especially in light of the fact that Bt is a soil bacterium that potentially interacts with and/or confronts these pathogens in their shared natural environment. Cry5B, like other Cry proteins, is predicted to have a high safety profile in vertebrates because its receptor is only found in invertebrates (Griffitts et al., Science, 307: 922-925, 2005). Cry5B has been shown to be nematicidal against every free-living nematode it was tested against (Wei et al., 2003) and that, when delivered per os (by mouth), cures hamsters of a human hookworm infection (Cappello et al., 2006 and Aroian et al., WO 2007/062064). These proteins, however, have not yet been approved for use in the treatment of STN infections.
Only four drugs (anthelmintics), which fall into two classes, are approved by the WHA for STN therapy: (1) the benzimidazoles (mebendezole (Meb), albendazole) and nicotinic acetylcholine receptor (nAChR) agonists (levamisole (Lev), pyrantel). The problem with having so few anthelmintic classes is the emergence of parasite resistance. In veterinary medicine, every parasitic nematode has been able to develop resistance to every class of anthelmintic, and for some animals, such as infected sheep, there are no treatment options left (Jabar et al., 2006). Although resistance to anthlemintics is suspected in Australia, Zanzibar, Vietnam, and Mali (Flohr et al., 2007; Stepek et al., 2006), STN resistance in human therapy is not widespread today. Experiences from veterinary helminth programs, however, paint a grim picture of the future if we take no action to prevent the emergence of resistance. This realization, as well as the lack of good anti-whipworm drugs, has evoked urgent and repeated cries for the development of new anthelmintics (e.g., Albonico, 2003; Keiser and Utzinger, 2008). It is therefore urgent that we act now while we still have options.